Editor's note
北京时间2024年9月11日，国际知名学术期刊《The Lancet Respiratory Medicine》全文发表了由上海交通大学附属胸科医院陆舜教授领衔开展的“Savolitinib in patients in China with locally advanced or metastatic treatment-naive non-small-cell lung cancer harbouring MET exon 14 skipping mutations: results from a single-arm, multicohort, multicentre, open-label, phase 3b confirmatory study”研究成果1。 此次发表是对2021年赛沃替尼关键II期临床试验成果的延续与深化，不仅再次获得该领域顶级期刊的高度认可，同时充分彰显了中国在创新药物研发及肺癌精准治疗领域的卓越成就与持续进步。 值此，医脉通特邀陆舜教授剖析这项研究的精髓与亮点，分享对MET 14号外显子跳跃突变（简称：MET 14跳突）非小细胞肺癌（NSCLC）精准诊疗的深刻见解和未来展望。
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With equal emphasis on efficacy and safety, savolitinib is an escort for patients with MET 14 skipping NSCLC
Savolitinib is a potent and highly selective oral MET-TKI following encouraging efficacy from data from a pivotal Phase II study demonstrating that savolitinib has been shown to have demonstrated encouraging efficacy in the treatment of MET 14 skipping NSCLC that has received prior systemic therapy or is unable to receive chemotherapy2. Based on these results, savolitinib was approved in China in June 2021, officially opening a new era of targeted therapy for advanced NSCLC with MET 14 skipping procedures.
The Phase IIIb confirmatory clinical study led by Prof. Shun Lu further strengthens savolitinib's position in the targeted treatment of MET 14 skipping advanced NSCLC. The full text reports the results of the Phase IIIb confirmatory clinical study in the first-line cohort of 87 treatment-naïve patients with locally advanced or metastatic MET 14 spike NSCLC who were given savolitinib 600 mg qd (≥50 kg) or 400 mg qd ( <50 kg). The primary endpoint of the study was objective response rate (ORR) as assessed by an independent review committee (IRC) according to RECIST 1.1. Secondary endpoints included disease control rate (DCR), duration of response (DoR), time to response (TTR), progression-free survival (PFS), and overall survival (OS).
The results showed that the median age of the patients was 70 years old, of which 58.6% were male, 80.5% had lung adenocarcinoma, 8.0% had pulmonary sarcomatoid carcinoma, and 11.5% had brain metastases. In the full analysis set (n=87), 54 patients assessed by IRC achieved partial response (PR) after savolitinib as first-line therapy, with an ORR of 62%, a DCR of 92%, a median TTR of 1.4 months, and a median DoR of 12.5 months. Tumor response was evaluable (n=84), with an ORR of 64% and a DCR of 95%. After a median follow-up of 18.0 months, the median PFS of patients assessed by IRC was 13.7 months, and OS was not reached.
Table 1: Efficacy data of patients evaluated by IRC and INV
Figure 1: PFS assessed by IRC
In terms of safety, common treatment-related adverse events included peripheral edema, increased alanine aminotransferase, increased aspartate aminotransferase, abnormal liver function, hypoalbuminemia, etc., and no new safety signals were found.
In summary, the study demonstrated the encouraging efficacy and manageable safety profile of savolitinib in the first-line treatment of locally advanced or metastatic NSCLC with MET 14 skips, providing a treatment option for treatment-naïve NSCLC patients with MET 14 skips.
Expert commentary
MET 14 jumps occur in about 3%~4% of adenocarcinoma patients, and are more common in non-smoking elderly female NSCLC patients3. At present, drugs targeting MET targets are emerging in an endless stream, including MET-TKI, monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, etc. As of September 2024, five highly selective MET-TKIs have been marketed in China, bringing hope and good news to Chinese patients. Among them, savolitinib, as the first MET-TKI approved for the indication of MET 14 skipping spikes in advanced NSCLC in China, has repeatedly attracted attention at important conferences such as AACR, WCLC, ELCC and other important conferences on the international stage, demonstrating its brilliant clinical data. In this Phase IIIb confirmatory study, savolitinib demonstrated significant anti-tumor activity in patients with MET 14 skip NSCLC in the first-line treatment, with a median PFS of 13.7 months, highlighting the potential of savolitinib to prolong patient survival and adding strong evidence for its expansion of the corresponding indications.
At the same time, the phase IIIb study showed that common treatment-related adverse reactions in patients, such as peripheral edema, alanine aminotransferase elevation, aspartate aminotransferase elevation, etc., are common adverse events of MET inhibitors, which can be well managed through dose adjustment and symptomatic treatment. Based on the published Chinese Multidisciplinary Expert Consensus on the Management of Savolitinib Adverse Reactions4, it will help to further guide the clinical management of savolitinib-related adverse reactions and maximize the benefits for patients.
It is worth noting that lung cancer treatment is characterized by long cycle, high cost and uncertain prognosis. Although several MET-TKIs have been approved for marketing in mainland China, the price of newly launched drugs is often expensive, and "looking forward to medicine" has become an unbearable burden for the majority of patients. In the past decade, the mainland has continued to strengthen the top-level design of the universal medical security system, and has built the world's largest basic medical security system. In March 2023, savolitinib was included in the National Reimbursement Drug List for the treatment of adult patients with locally advanced or metastatic NSCLC with MET 14 skipping spikes who have progressed after platinum-based chemotherapy or are intolerant to standard platinum-based chemotherapy, and will be implemented nationwide. This policy has been a boon for patients with MET 14 skip NSCLC, greatly reducing their financial burden and improving access to treatment. With the announcement of the first-line cohort results of the Phase IIIb study, we look forward to receiving approval for first-line indications and inclusion in medical insurance in the future, benefiting more patients with MET 14 skipping lung cancer.
All in all, savolitinib, a locally innovative MET-TKI, is not only a precise targeted treatment for patients with MET 14 skipping NSCLC, but also a wonderful display of China's drug R&D strength in the field of global cancer treatment. However, resistance to MET-TKIs is inevitable, and we are not resting there. On the contrary, the scientific community is taking an unprecedented level of determination and dedication to delve into the complex mechanisms of drug resistance in order to break through this therapeutic bottleneck. It is believed that with the increasing abundance of evidence-based medical evidence and the continuous emergence of scientific and technological innovation, more treatment options can be brought to patients with MET 14 skipping spike NSCLC!
Expert Profile
Prof. Shun Lu
- Shanghai Chest Hospital, Shanghai Jiao Tong University Chest Hospital, Director of Shanghai Pulmonary Tumor Clinical Medical Center
- Chief Physician, Doctoral Supervisor, Second-level Professor, Young and Middle-aged Expert with Outstanding Contributions to National Health, Shanghai Leading Talent, Shanghai Outstanding Academic Leader, Chief Expert of National Key Projects, Special Allowance of the State Council, Director of Collaborative Innovation of Biomedical Clinical Research and Transformation of Shanghai Municipality of the Ministry of Education
- Member of the Academic Committee of Shanghai Jiao Tong University School of Medicine
- Former Chairman of the Lung Cancer Committee of the Chinese Anti-Cancer Association
- Executive Director of the Chinese Society of Clinical Oncology (CSCO) and Vice Chairman of the Hisco Foundation
- Former Chairman of the DIA China Advisory Board
- External expert of drug review of the State Food and Drug Administration
- Former Chairman of the Oncology Society of Shanghai Medical Association
- Member of the Standing Committee of the Oncology Society of the Chinese Medical Association, Chairman of the Lung Cancer Expert Committee
- President of the Oncology Branch of Shanghai Medical Doctor Association
- He is a former member of the ASCO Asia Committee and a member of the JSMO International Committee
- 国际肺癌研究会官方杂志Journal of Thoracic Oncology副主编，Lung Cancer 副主编，The Oncologist杂志编委
- Executive Director of Shanghai Anti-Cancer Association
- Vice Chairman of the Precision Medicine Branch of the China Pharmaceutical Biotechnology Association
- As the person in charge, he presided over the national key projects of chronic diseases and international cooperation projects of the Ministry of Science and Technology; National New Drug Innovation Major Project, 2 sub-projects of 863 major projects; Key projects of the National Natural Science Foundation of China, lung cancer special projects and general projects
- First Prize of Science and Technology Award of China Anti-Cancer Association; First Prize of Shanghai Medical Science and Technology Award; Second Prize of Huaxia Medical Science and Technology Award; First Prize of Shanghai Science and Technology Progress Award; President's Award of Shanghai Jiao Tong University; In 2018, he was nominated for the · Shanghai Outstanding Specialist Physician Award, and in 2021, he won the "WuXi AppTec Life Chemistry Research Award"
Bibliography:
1．Y. Yu, Q. Guo, Y. Zhang, et al. Savolitinib in patients in China with locally advanced or metastatic treatment-naive non-small-cell lung cancer harbouring MET exon 14 skipping mutations: results from a single-arm, multicohort, multicentre, open-label, phase 3b confirmatory study. The Lancet Respiratory Medicine.
2．Lu S, Fang J, Li X, et al. Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: a multicentre, single-arm, open-label, phase 2 study. Lancet Respir Med. 2021; 9(10):1154-1164.
3．Fujino, Toshio et al. Lung Cancer with MET exon 14 Skipping Mutation: Genetic Feature, Current Treatments, and Future Challenges. Lung Cancer (Auckl). 2021 May 20;12:35-50.
4. Zhang Li, Wang Yongsheng, Lin Lizhu, et al. Chinese multidisciplinary expert consensus on the management of savolitinib-related adverse reactions. Chinese Journal of Oncology, 2023, 45(04):298-312.
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